The present invention relates to a stable gel formulation for the topical application of a combination of an imidazole antifungal agent and a 17-ester steroid antiinflammatory agent. The product is particularly suitable for treating fungal diseases such as tinea capitis, tinea corporis or tinea cruris. Decomposition of the 17-ester steroid resulting from interaction with water and the imidazole antifungal agent during storage is drastically reduced by the present gel formulation.
A fungus is a very small microscopic type of plant cell which may grow on the skin and, under certain conditions, produce an infection. Such infections caused by fungi, the mycoses, are among the oldest known to man and have long been recognized as a highly prevalent public health problem. When the fungus infection involves the scalp, it is known as tinea capitis; when it involves the feet it is known as tinea pedis (athlete's foot); when it occurs on the body it is known as tinea corporis; and when it occurs in the groin it is known as tinea cruris.
A variety of methods have been used for the treatment of fungal infections including the use of potassium iodide, Whitfield's ointment, undecylenic acid, antibiotics (e.g. nystatin and amphotericin B), griseofulvin and the imidazole antifungal agents such as miconazole, clotrimazole, econazole and sulconazole.
Although the systemic administration of antibiotics such as nystatin and amphotericin B has been used with some success, the low bioavailability and systemic toxicity of these agents have restricted their use in treating mycotic infections.
The imidazoles are the first broad-spectrum antifungals and are of considerable importance in clinical practice. Their broad spectrum of antifungal activity, extending to most pathogenic fungi, has provided an important advance in antifungal therapy.
As used herein the term "imidazole antifungal agent" means any agent having an imidazole functional group in the molecule and possessing topical antifungal activity. A large number of suitable imidazoles have been described in the literature and are well-known to those skilled in the art. Examples of suitable imidazole antifungal agents include sulconazole nitrate, econazole nitrate, miconazole nitrate and clotrimazole.
The fungal infections are commonly associated with signs of erythema and scaling and with symptoms of itching or painful burning. Clinical treatment for fungal disease requires at least two to four weeks for complete relief of symptoms. More recently, it has been found that fungal infections can be effectively treated with a combination product containing corticosteroids and imidazole antifungal agents. It is known that the sensitivity of fungal organisms varies with their life cycles; spores are more resistant to treatment than are mycelia. Steroids may induce fungal spores to produce mycelia, thereby making them more sensitive to treatment. Also, steroids are known to produce vasoconstriction at the site of application. This activity may delay or prevent the elimination of the antifungal agent from the application site, permitting the antifungal agent to remain in the epidermis for longer periods of time. It is therefore believed that a locally applied antiinflammatory agent would offer direct and immediate relief for the inflammatory component of the lesion. The combination product should then provide fast relief of symptoms and eradicate the infection. Based on this concept, certain combinations of an antifungal agent and an antiinflammatory agent have recently been developed for treatment of fungal disease. Currently, the commercially available combination products using this concept are Lotrisone cream (clotrimazole 1%/betamethasone dipropionate 0.05%), Daktacort cream (miconazole nitrate 2%/hydrocortisone 1%) and Canesten HC cream (clotrimazole 1%/hydrocortisone 1%).
Katz and other dermatologists.sup.1,2 found that Lotrisone cream was therapeutically and mycologically better than clotrimazole 1% and betamethasone dipropionate 0.05% alone. Notwithstanding its clinical advantages, Lotrisone cream possesses some undesirable attributes. It contains a rather strong fluorinated steroid, betamethasone dipropionate, which can be quite cosmetically dangerous to use in intertrigious regions. Other undesirable attributes include skin atrophy, rebound phenomenon and telengiectasia.
Other marketed combination products of this type, e.g. Daktacort cream and Canesten HC cream, are combinations of low-potency steroids and imidazoles. Such combination products always fail to provide the fast relief of the inflammatory symptoms which is normally desired for the treatment of a fungal infection.
A combination of a non-halogenated mid-potency steroid and an imidazole antifungal agent would appear to be an ideal choice for the topical treatment of fungal disease. It was the object of the present invention to develop such a combination product.
The mid-potency steroid used in the combination product of the present invention is a 17-ester steroid which possesses enhanced activity relative to the parent alcohol but fewer undesirable side effects than the halogenated steroids which are comparable in activity. Examples of 17-ester corticosteroids included within the scope of the invention are hydrocortisone 17-acetate, hydrocortisone 17-butyrate, hydrocortisone 17-valerate, hydrocortisone 17-propionate, betamethasone 17-valerate, cortisone 17-acetate, prednisone 17-acetate and prednisone 17-valerate.
The 17-ester steroids per se have excellent stability in conventional topical dosage forms. In our studies topical dosage forms are tested for stability by determinining their t.sub.90% values where t.sub.90% is the time in days required for a dosage form to lose 10% of its chemical and/or biological activity. A 0.2% hydrocortisone 17-valerate o/w cream in this test had a t.sub.90% of 536 days at room temperature (25.degree. C..+-.2.degree. C.). Use of a standard 10% overage of active ingredient in the cream would mean that such a product would have an acceptable shelf life (time required for potency to decrease to 90% of label strength) at room temperature of 1072 days or more than 2.9 years.
A cream formulation is generally more acceptable to a patient than other topical dosage forms, e.g. liquid, petrolatum ointment, oil, etc., from the point of view of aesthetics and ease of application. Unfortunately, when one attempts to combine a 17-ester steroid and an imidazole antifungal agent to make a combination product as described above, the stability of the 17-ester steroid is drastically reduced to unacceptable levels in almost all conventional cream formulations. To develop a cream vehicle for a combination product of a 17-ester steroid and an imidazole, we have prepared for stability evaluation more than 60 different types of cream vehicles including o/w creams, w/o creams, creams with high or low petrolatum content, with low or high surfactant content, with high or low water content, and with different propylene glycol content. Almost all creams failed our stability test, either due to the chemical instability of the 17-ester steroids or the physical separation of emulsion caused by the salting effect of the imidazole salt when used in concentrations of about 1% or more. Cream formulations often necessitate the use of emulsifiers or surfactants to maintain their physical stability and the use of antimicrobial preservatives to prevent microbiological contamination. These additives tend to generate an undesirable environment which can accelerate the hydrolysis of 17-ester steroids and the physical separation due to the salting out. In addition, it is known that imidazoles can also be catalysts for the hydrolysis of esters.sup.3-7. Such degradation was in fact observed in our preliminary studies (see Table I below).
TABLE 1 ______________________________________ Degradation rates of hydrocortisone 17-valerates (HC 17-V) in the presence of 1% imidazoles in various topical creams at 25.degree. C. .+-. 2.0.degree. C. t.sub.90%, Formulations k, day.sup.-1 **** days*** ______________________________________ 1. Sulconazole nitrate 1%/ 3.07 .times. 10.sup.-3 34 HC 17-V 0.2% in aqueous- alcohol solution at pH 4.7 2. Sulconazole nitrate 1%/ 5.96 .times. 10.sup.-3 18 HC 17-V 0.2% in o/w cream at pH 4.7 3. Sulconazole nitrate 1%/ 7.40 .times. 10.sup.-3 14 HC 17-V 0.5% in USP XXI Oint. at 4.7 4. Sulconazole nitrate 1%/ 6.50 .times. 10.sup.-3 16 HC 17-V 0.2% in Carbapol* gel 5. Sulconazole nitrate 1%/ physical HC 17-V 0.2% in Methocel** separation gel 6. Sulconazole nitrate 1%/ 2.24 .times. 10.sup.-3 47 HC 17-V 0.2% in pure petrolatum base 7. Econazole nitrate 1%/ 1.34 .times. 10.sup.-2 7.8 HC 17-V 0.2% in USP XXI hydrophilic ointment 8. Miconazole nitrate 1%/ 2.99 .times. 10.sup.-2 3.5 HC 17-V 0.2% in o/w cream 9. Miconazole nitrate 1%/ 4.28 .times. 10.sup.-2 2.5 HC 17-V 0.2% in USP XXI hydrophilic ointment 10. Clotrimazole 1%/HC 17-V 4.39 .times. 10.sup.-3 24 0.2% in o/w cream 11. Clotrimazole 1%/HC 17-V 2.26 .times. 10.sup.-2 4.6 0.2% in USP XXI hydrophilic ointment ______________________________________ *Carbopol gel is a carboxy vinyl polymer of high molecular weight (CTFA names: carbomer934p, 940, 961 **Methocel gel is the methyl ether of cellulose (CTFA name: methylcellulose, trade names: Methocel MC, Cellulose Methyl Ether). ***t.sub.90% = time required for hydrocortisone 17valerate activity to be reduced to 90% of original ****k = degradation rate of hydrocortisone 17valerate component
Based on our studies it is believed that the necessity of using emulsifiers or surfactants in most cream formulations results in increased interaction of the 17-ester steroid with water and imidazole molecules, thereby causing rapid hydrolysis of the 17-ester steroid (see Table I, formulations 2, 3 and 7-11).
Several commonly used gel formulations prepared without any emulsifier or surfactant and with a gelling agent selected from a group consisting of an acidic carboxy polymer, such as those available under the trade names Carbopol 934, Carbopol 940, and a methyl ether of cellulose available under the trade name Methocel MC, were used for combination products. As shown in Table I, formulations 4 and 5, a fast degradation at the carbon-17 position of the 17-ester steroids was still observed.
Moreover, in a subsequent experiment, a mixture of an imidazole with hydrocortisone 17-valerate also showed rapid hydrolysis even in pure petrolatum. Poor dispersibility is considered the cause of the stability failure in the pure petrolatum system (see Table I, formulation 6).
Since ester hydrolysis is known to be affected by pH, the stability of an imidazole with a 17-ester steroid o/w cream system adjusted to different pHs was studied. The results (Table II) show that simple pH adjustment will not impart the required stability.
TABLE II ______________________________________ Degradation rates of hydrocortisone 17-valerate 0.2% in the presence of 1% sulconazole nitrate in USP XXI hydrophilic ointment (an o/w cream) at 25.degree. C. .+-. 2.0.degree. C. at different pH. pH k, day.sup.-1 t.sub.90%, days ______________________________________ 2.10 2.10 .times. 10.sup.-3 50 4.00 3.80 .times. 10.sup.-3 28 4.70 4.45 .times. 10.sup.-3 24 6.50 5.20 .times. 10.sup.-3 20 ______________________________________
In order to prevent the degradation of hydrocortisone and its derivatives in topical formulations, it has been proposed to use the steroid active ingredient in association with certain stabilizers (e.g. EDTA, antioxidants) or to reduce the amount of propylene glycol used in the formulation.sup.8-10. Despite using stabilizers or reducing the concentration of propylene glycol in the steroid formulations of the prior art, it has not been possible to obtain topical solutions, gels or creams of a combination product having acceptable (two years or more) long term stability.
To fulfill the unmet needs, it remained highly desirable to obtain a combination of an imidazole antifungal agent and a 17-ester antiinflammatory corticosteroid in a topical dosage form which would be stable for at least two years at room temperature (25.degree..+-.2.degree. C.). It was an object of the present invention to provide such a stable combination product from which the imidazole and 17-ester steroid would be readily available for absorption by the skin. It was also an object to provide a combination product formulation which could be applied to the affected skin, e.g. the intertrigious area, without flowing onto the healthy parts of the skin. This latter property would minimize the undesirable side effects that might be caused by absorption through surrounding tissue. Such a combination product then, would not only provide fast relief of symptoms and the eradication of the fungal infection but would also minimize the risk of undesirable side effects.
It was a further object of the present invention to provide a topical antifungal treatment which can effectively provide fast relief of symptoms and eradication of the fungal infection while minimizing the risk of undesirable side effects caused by high-potency and/or fluorinated steroids.
It was another object of the invention to provide topical gel formulations of mid-potency 17-ester steroids and imidazole antifungal agents which possess good dispersibility and good physical and chemical stability without refrigeration and without the need for special additives such as emulsifiers or surfactants or antimicrobial preservatives.
It was another object of the invention to provide topical gel formulations of 17-ester steroids and imidazoles having other desirable qualities such as being cosmetically acceptable and allowing accurate application of effective amounts of the two active ingredients to the desired lesion.
It was still another object of the invention to provide topical gel formulations which enhance delivery of a 17-ester steroid and imidazole to their respective target sites, thereby ensuring that a maximum therapeutic advantage could be achieved.
These and other objects of the present invention will be more fully understood in the light of the specific examples and description set forth below.